Microwave assisted synthesis of 2-aminooxazolo [4,5-b] pyridine derivatives via intramolecular C-O bond formation in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2013.12.090

A highly, efficient synthetic protocol for the synthesis of 2-aminooxazolo[4,5-b]pyridine derivatives is established via intramolecular C-O bond coupling using copper iodide as a catalyst and water as solvent. A variety of functionalized substrates were found to react under this reaction conditions to provide products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.12.090

Tetrahedron Letters 55 (2014) 1296–1298
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted synthesis of 2-aminooxazolo [4,5-b] pyridine
derivatives via intramolecular C–O bond formation in aqueous
medium
Umesh B. Kosurkar a, Tulshiram L. Dadmal a, K. Appalanaidu a, Y. Khageswara Rao a, Jagadeesh B. Nanubolu b,
Ravindra M. Kumbhare a,
⇑
a Fluoroorganic Division, Indian Institute of Chemical Technology, CSIR, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, CSIR, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly, efficient synthetic protocol for the synthesis of 2-aminooxazolo[4,5-b]pyridine derivatives is
established via intramolecular C–O bond coupling using copper iodide as a catalyst and water as solvent.
A variety of functionalized substrates were found to react under this reaction conditions to provide prod-
ucts in good to excellent yields.
Ó 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/3.0/).
Received 11 October 2013
Revised 24 December 2013
Accepted 25 December 2013
Available online 3 January 2014
Keywords:
Aqueous reaction
C–O bond formation
Copper iodide
Isothiocyanate
Microwave
In recent years, an intramolecular carbon–oxygen cross cou-
pling chemistry for the synthesis of benzoxazole employing copper
catalysis is reported.1 Pyridine nucleus found in many alkaloids
such as Ricicine, Nicotine, Anabasine, Myosmin, etc. is considered
as valued biological active compounds. Heterocycles fused with
pyridine nucleus resulted in anticancer,2 antipyretic,3 and anticon-
vulsant activities.4 The recent literature5 showed that pyridine
derivatives worked well on breast cancer cell line MDA-MB-231,
MCF-7. Oxazole containing compounds possess anticancer and
anti-HIV-1 properties,6,7 leukemia and potent selective 5-HT1A
serotonin receptor ligands,8 and some other useful activities.9–12
Pyridine analog of benzoxazole possess biological activity13 and
fluorinated analog of 2-aminooxazolo[5,4-b] pyridine derivatives
is an important candidate for the treatment of Alzheimer disease.14
Classical method15 for the synthesis of 2-aminooxazolo[4,5-b]
pyridine involves the use of silver nitrate which is toxic, corrosive
and requires harsh reaction condition. Other methods16 by use of
volatile solvents take more time. To the best of our knowledge
there is no report for the synthesis of 2-aminooxazolo[4,5-b]
pyridine derivatives from the 2-amino-3-hydroxypyridine in aque-
ous medium. Therefore the development of an efficient method for
its construction is highly desirable for drug discovery. Hence in
continuation of our efforts to develop the efficient procedure for
the preparation of heterocyclic entities,17 herein we describe the
microwave assisted synthesis of 2-aminooxazolo[4,5-b] pyridine
derivatives with more yield in less time using inexpensive and
non-toxic copper iodide which provides the efficient strategy for
the C–O cross coupling.
Microwave technology shortens the reaction time, provides bet-
ter yield and high purity in chemical transformation. Microwave
accelerated one pot reactions have been applied recently.18 In re-
cent years, use of water as reaction media has gained much inter-
est. In industries around 80% of the waste are produced by the use
of organic solvents.19,20 Water is abundant, cheap, nonflammable,
nontoxic, and green solvent. Selectivity and reactivity in reaction
carried out in aqueous media can be achieved due to chemical
and physical properties of water which cannot be possible using
organic solvents (Scheme 1).21–23
In order to optimize the reaction condition, we have selected
the synthesis of 2-aminooxazolo [4,5-b] pyridine as a model reac-
tion (Table 1). Initially, we carried out the reaction in water with
and without catalysts at room temperature but there is no progress
of reaction. Later on heating in water without catalyst using
triethylamine as base for 5 h, we observed less yield (21%).
Reaction resulted into good yield (85%) on conventional heating
⇑
Corresponding author. Tel.: +91 40 27191776; fax: +91 40 27193185.
E-mail address: rakumbhare@yahoo.com (R.M. Kumbhare).
http://dx.doi.org/10.1016/j.tetlet.2013.12.090
0040-4039/Ó 2014 Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

U. B. Kosurkar et al. / Tetrahedron Letters 55 (2014) 1296–1298
1297
Ag+
Table 2
Previous work15
Copper iodide catalyzed C–O bond formation
Entry Product
Time (min)
4
Yielda (%)
OH
O
O
N
O
H
N
NR1R2
S
3a
3b
3c
88
84
83
N
NHCSNR1R2
N
H
N
N
O
N
N
N
N
N
R1= alkyl, phenyl; R2 = H, C2H5
H
N
F
5
5
This design
N
O
H
N
OH
O
Cl
H
H2O, MW
SCN R2
N
R2
N
O
R1
N
NH2
CuI, 4min
R1
N
N
H
N
Cl
R1 = H, CH3, R2 = n-Bu, benzyl, Cyh, Ar
N
3d
3e
4
4
84
86
CF3
Scheme 1. Comparison of previous work with our design.
O
N
H
N
Br
N
F3C
Table 1
Catalyst optimization
O
N
O
N
O
H
N
CH3
3f
4
5
83
81
N
N
N
NCS
OH
H
N
O
N
H
N
OCH3
3g
N
NH2
N
H
N
3h
5
80
Entry
Cu catalyst (5 mol %)
Power (W)
Time (min)
Yielda (%)
N
1
2
3
4
5
6
CuCl
CuBr
CuI
Cu2O
Cu(SO4)2
Cu(OAC)2
540
540
360
540
540
540
6
6
4
5
6
7
70
72
88
53
58
66
O
N
O
N
O
N
H
N
CF3
3i
3
5
5
4
4
4
4
5
90
78
76
90
85
84
83
82
N
N
N
H
N
3j
Note: Bold value indicate the reaction condition.
Reaction condition: 2-amino-3-hydroxy pyridine (1 mmol), Phenyl isothiocyanate
(1 mmol), Et3N (4 mmol), CuI, 360 W at 100 °C and water as solvent.
N
H
3k
3l
O
H
N
a
Isolated yield.
N
O
N
N
N
N
N
N
H
N
F
3m
3n
3o
3p
N
O
at 90 °C using CuI as catalyst in water solvent for 3 h. But when
reaction was carried out under microwave irradiation using
different catalysts (Table 1), CuI showed better yield in shorter
time. So we selected microwave method for the reaction. Copper
iodide is responsible for cyclodesulfurization by removing sulfur
from 1-(3-hydroxypyridin-2-yl)-3-phenylthiourea in the form of
Cu2S as black precipitate and develops the intramolecular C–O
cross coupling. Further product of the reaction 3o was confirmed
by X-ray crystallography24 (Fig. 1).
Our observation in the change of yield concludes that yield
depends on the electrophilicity of isothiocyanate and nucleophilicity
of 2-amino-3-hydroxy pyridine. Now, to study the viability of reac-
tion, a series of substrates were studied (Table 2).25 The 3-hydroxy-
2-amino pyridine and its 6-methyl analog do not show a significant
change in the yield of the products. Electron withdrawing substitu-
ent on phenyl isothiocyanate increases the yield of product while
electron donating substituent decreases the yield, giving 3r in high
H
N
Cl
N
O
H
N
CH3
OCH3
N
O
H
N
N
O
H
N
3q
3r
3s
5
3
3
81
92
88
N
O
N
O
H
N
CF3
N
N
H
N
Cl
N
CF3
O
H
N
Br
3t
3
91
N
N
F3C
O
N
O
N
H
N
3u
3v
5
5
79
78
N
N
N
H
a
Isolated yields.
yield. When pyridine substrate was treated with cyclohexyl and
n-butyl isothiocyanate, the reaction results in less yield of the
products compared to aromatic isothiocyanate. This is attributed
to the decrease in electrophilicity of isothiocyanate carbon.
Figure 1. ORTEP molecular diagram of 3o.

1298
U. B. Kosurkar et al. / Tetrahedron Letters 55 (2014) 1296–1298
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O
N
H
H
N
-Cu2S
N
N
H
SH
N
N
3a
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Scheme 2. A plausible mechanism for the synthesis of 3a.
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A plausible mechanism for the synthesis of 3a is depicted below
(Scheme 2).
In summary, we have developed a novel, one pot, and versatile
method for the synthesis of 2-aminooxazole[4,5-b]pyridine via
intramolecular C–O bond coupling using copper iodide as a catalyst
in aqueous solvent using microwave technology. Starting materials
used are readily available, inexpensive, and harmless. The proce-
dure is extremely useful in synthetic and medicinal chemistry. As
this method is conducted in aqueous solvent which is economically
and environmentally benign solvent, it can be applicable in
industry.
17. (a) Kumbhare, Ravindra M.; dadmal, Tulshiram; Kosurkar, Umesh; Vijay
Kumar, K. J. Heterocycl. Chem. 2012, 49, 342; Umesh B. Kosurkar; Tulshiram
L. Dadmal; Ravindra M. Kumbhare; Balasubramanian Sridhar, J. Heterocycl.
Chem. 2013, in press, http://dx.doi.org/10.1002/jhet.1812.
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Acknowledgments
21. (a) Grieco, P. A. Organic Synthesis in Water; Blackie: London, 1998; (b) Li, C. J.;
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Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem. 2006, 71, 3634; (c) Tiwari, S.;
Kumar, A. Angew. Chem. 2006, 118, 4942. Angew. Chem., Int. Ed. 2006, 45, 4824.
24. CCDC 964599 contains the supplementary crystallographic data for this
We are thankful to the Director of IICT for providing facilities.
U.K., K.A. and Y.K. thank CSIR and T.D. thanks UGC, New Delhi,
for the award of a fellowship and R.M.K. thanks S.E.R.C., Depart-
ment of Science & Technology, Government of India for financial
assistance under the Fast Track Scheme for young scientists (SR/
FTP/CS-031/2010).
paper. Crystal data for 3o:
C14H13N3O, M = 239.27, colourless block,
Supplementary data
0.39 Â 0.24 Â 0.18 mm3, monoclinic, space group P21/c (No. 14), a = 6.1565(6),
b = 17.7411(16), c = 12.1353(9) Å, b = 15.779(4)°, V = 1193.54(18) Å3, Z = 4,
Dc = 1.332 g/cm3, F000 = 504, CCD area detector, Mo-K
a
radiation,
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.090.
k = 0.71073 Å, T = 293(2) K, 2hmax = 50.0°, 11,333 reflections collected, 2105
unique (Rint = 0.0258), Final GooF = 0.898, R1 = 0.0430, wR2 = 0.1169, R indices
based on 1916 reflections with I >2
= 0.087 mmÀ1
r
(I) (refinement on F2), 169 parameters,
l
.
25. Typical experimental procedure: In seal tube, the mixture of 2-amino-3-hydroxy
pyridine (0.1 g, 1 mmol), Phenyl isothiocyanate (1 mmol), Triethylamine
(4 mmol) and CuI (5 mol %) were added in water (2 mL) and the reaction
mixture was microwave irradiated at 360 W for 4 min at 100 °C. After the
completion of reaction (monitored by TLC), water added to the reaction
mixture and extracted with ethyl acetate. Organic layer washed with brine
solution (2 Â 20 mL) and dried over anhydrous Na2SO4. Solvent was
evaporated under reduced pressure to give crude product which was further
purified by Silica gel column chromatography (20% EtOAc/n-Hexane) to give 3a
(0.17 g, 88%).
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Spectral data for N-phenyloxazolo[4,5-b]pyridin-2-amine (3a): White solid; mp
261–263 °C; IR (KBr): 3374, 2875, 1651, 1548, 1423, 1221 cmÀ1 1H NMR
;
(300 MHz, DMSO) dH: 10.61 (1H, s, NH), 8.34–8.19 (1H, m, ArH), 7.92–7.54 (3H,
m, ArH), 7.47–7.28 (2H, m, ArH), 7.18–6.98 (2H, m, ArH); 13C NMR (300 MHz,
DMSO) dC : 158.8, 155.9, 142.7, 138.4, 136.6, 127.4, 121.4, 116.9, 115.3, 113.9;
HRMS: m/z calcd for C12H10ON3 (M+H)+ : 212.0818; found 212.0813.
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